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Reaction Between Grignard reagents and Heterocyclic N-oxides: Synthesis of Substituted Pyridines, Piperidines and Piperazines
Umeå University, Faculty of Science and Technology, Chemistry. (Fredrik Almqvist)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the development of new synthetic methodologies for preparation of bioactive interesting compounds, e.g. substituted pyridines, piperidines or piparazines. Thesecompounds are synthesized from commercially available, cheap and easily prepared reagents, videlicet the reaction between Grignard reagents and heterocyclic N-oxides.

 The first part of this thesis deals with an improvement for synthesis of dienal-oximes and substituted pyridines. This was accomplished by a rapid addition of Grignard reagents to pyridine N-oxides at rt. yielding a diverse set of substituted dienal-oximes. During these studies, it was observed that the obtained dienal-oxmies are prone to ring-close upon heating. By taking advantage of this, a practical synthesis of substituted pyridines was developed.

In the second part, an ortho-metalation of pyridine N-oxides using Grignard reagents is discussed. The method can be used for incorporation of a range of different electrophiles, including aldehydes, ketones and halogens. Furthermore, the importance for incorporation of halogens are exemplified through a Suzuki–Miyaura coupling reaction of 2-iodo pyridine N-oxides and different boronic acids. Later it was discovered that if the reaction temperature is kept below -20 °C, the undesired ringopening can be avoided. Thus, the synthesis of 2,3-dihydropyridine N-oxide, by reacting Grignard reagents with pyridine N-oxides at -40 °C followed by sequential addition of aldehyde or ketone, was accomplished. The reaction provides complete regio- and stereoselectivity yielding trans-2,3-dihydropyridine N-oxides in good yields. These intermediate products could then be used for synthesis of either substituted piperidines, by reduction, or reacted in a Diels–Alder cycloaddtion to give the aza-bicyclo compound.

In the last part of this thesis, the discovered reactivity for pyridine N-oxides, is applied on pyrazine N-oxides in effort to synthesize substituted piperazines. These substances are obtained by the reaction of Grignard reagents and pyrazine N-oxides at -78 °C followed by reduction and protection, using a one-pot procedure. The product, a protected piperazine, that easily can be orthogonally deprotected, allowing synthetic modifications at either nitrogens in a fast and step efficient manner. Finally, an enantioselective procedure using a combination of PhMgCl and (-)-sparteine is discussed, giving opportunity for a stereoselective synthesis of substituted piperazines.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2009. , 63 p.
Keyword [en]
Grignard reagents, pyridine N-oxide, pyrazine N-oxide, dienal-oxime, pyridine, ortho- metalation, piperidine, piperazine, asymmetric
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-25619ISBN: 978-91-7264-844-9 (print)OAI: oai:DiVA.org:umu-25619DiVA: diva2:232682
Distributor:
Kemi, 90187, Umeå
Public defence
2009-09-25, Naturvetarhuset N360, Umeå Universitet, Umeå, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-09-04 Created: 2009-08-25 Last updated: 2009-09-04Bibliographically approved
List of papers
1. Reaction of pyridine N-oxides with Grignard reagents: a stereodefined synthesis of substituted dienal oximes
Open this publication in new window or tab >>Reaction of pyridine N-oxides with Grignard reagents: a stereodefined synthesis of substituted dienal oximes
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2007 (English)In: Tetrahedron Letters, Vol. 48, 6941-4 p.Article in journal (Refereed) Published
Abstract [en]

Rapid addition of Grignard reagents to pyridine N-oxides under mild conditions gave stereodefined dienal oximes in good to excellent yields. This reaction provides an efficient access to substituted olefins with defined stereochemistry that are potentially of interest as bioactives themselves or as versatile synthetic intermediates.

Identifiers
urn:nbn:se:umu:diva-16188 (URN)doi:10.1016/j.tetlet.2007.07.161 (DOI)
Note
Available online 28 July 2007Available from: 2007-08-30 Created: 2007-08-30 Last updated: 2010-01-08Bibliographically approved
2. Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents
Open this publication in new window or tab >>Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents
2008 (English)In: Tetrahedron Letters, Vol. 49, no 48, 6901-3 p.Article in journal (Refereed) Published
Abstract [en]

Addition of i-PrMgCl to pyridine N-oxides in THF at −78 °C generates selectively an ortho-metallated species, which can be trapped with various electrophiles to generate 2-substituted pyridine N-oxides. Furthermore, by applying a double metal-catalyzed cross-coupling, direct arylation of the pyridine N-oxides is achieved.

Identifiers
urn:nbn:se:umu:diva-10629 (URN)doi:10.1016/j.tetlet.2008.09.104 (DOI)
Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2010-01-08Bibliographically approved
3. Synthesis of 2-Substituted Pyridines via a Regiospecific Alkylation, Alkynylation, and Arylation of Pyridine N-Oxides
Open this publication in new window or tab >>Synthesis of 2-Substituted Pyridines via a Regiospecific Alkylation, Alkynylation, and Arylation of Pyridine N-Oxides
2007 (English)In: Organic Letters, Vol. 9, no 7, 1335-7 p.Article in journal (Refereed) Published
Abstract [en]

Sequential addition of Grignard reagents to pyridine N-oxides in THF at room temperature followed by treatment with acetic anhydride at 120 C afforded 2-substituted pyridines in good to high yields. Furthermore, by exchanging acetic anhydride for DMF in the second step, 2-substituted pyridine N-oxides were obtained, as intermediates suitable for addition of a second Grignard reagent for the synthesis of 2,6-disubstituted pyridines.

Identifiers
urn:nbn:se:umu:diva-12793 (URN)doi:10.1021/ol070184n (DOI)
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2010-01-08Bibliographically approved
4. The Regio- and Stereoselective Synthesis of trans-2,3-Dihydropyridine N-oxides and Piperidines
Open this publication in new window or tab >>The Regio- and Stereoselective Synthesis of trans-2,3-Dihydropyridine N-oxides and Piperidines
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2009 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 48, no 18, 3288-3291 p.Article in journal (Refereed) Published
Abstract [en]

No Abstract

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlagsgesellschaft, 2009
Keyword
heterocycles, grignard reagents, regioselectivity, synthetic methods
National Category
Physical Sciences Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-20832 (URN)10.1002/anie.200900189 (DOI)
Available from: 2009-03-26 Created: 2009-03-26 Last updated: 2017-12-13Bibliographically approved

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